Chemical formula: C₂₁H₂₅NO₃ Molecular mass: 339.435 g/mol
Nalmefene is an opioid system modulator with a distinct μ, δ, and κ receptor profile.
In vitro studies have demonstrated that nalmefene is a selective opioid receptor ligand with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor.
In vivo studies have demonstrated that nalmefene reduces alcohol consumption, possibly by modulating cortico-mesolimbic functions.
Data from the nonclinical studies, the clinical studies, and the literature do not suggest any form of dependence or abuse potential with nalmefene.
Nalmefene is rapidly absorbed after a single oral administration of 18.06 mg, with a peak concentration (Cmax) of 16.5 ng/ml after approximately 1.5 hours and an exposure (AUC) of 131 ng*h/ml.
The absolute oral bioavailability of nalmefene is 41%. Administration of high-fat food increases the total exposure (AUC) by 30% and the peak concentration (Cmax) by 50%; the time to peak concentration (tmax) is delayed by 30 min (tmax is 1.5 hours). This change is considered unlikely to be of clinical relevance.
The average protein-bound fraction of nalmefene in plasma is approximately 30%. The estimated volume of distribution (Vd/F) is approximately 3200 l.
Occupancy data obtained in a PET study after single and repeated daily dosing with 18.06 mg nalmefene show 94% to 100% receptor occupancy within 3 hours after dosing, which suggests that nalmefene readily crosses the blood-brain barrier.
Following oral administration, nalmefene undergoes extensive, rapid metabolism to the major metabolite nalmefene 3-O-glucuronide, with the UGT2B7 enzyme being primarily responsible for the conversion, and with the UGT1A3 and UGT1A8 enzymes as minor contributors. A small proportion of nalmefene is converted to nalmefene 3-O-sulphate by sulphation and to nornalmefene by CYP3A4/5. Nornalmefene is further converted to nornalmefene 3-O-glucuronide and nornalmefene 3-O-sulphate. The metabolites are not considered to contribute with significant pharmacological effect on the opioid receptors in humans, except for nalmefene 3-O-sulphate, which has a potency comparable to that of nalmefene. However, nalmefene 3-O-sulphate is present in concentrations less than 10% of that of nalmefene and thus considered highly unlikely to be a major contributor to the pharmacological effect of nalmefene.
Metabolism by glucuronide conjugation is the primary mechanism of clearance for nalmefene, with renal excretion being the main route of elimination of nalmefene and its metabolites. 54% of the total dose is excreted in the urine as nalmefene 3-O-glucuronide, while nalmefene and its other metabolites are present in the urine in amounts of less than 3% each.
The oral clearance of nalmefene (CL/F) was estimated as 169 l/h and the terminal half-life was estimated as 12.5 hours.
From distribution, metabolism, and excretion data, it appears that nalmefene has a high hepatic extraction ratio.
Nalmefene exhibits a dose-independent linear pharmacokinetic profile in the dose interval of 18.06 mg to 72.24 mg, with a 4.4 times increase in Cmax and a 4.3 times increase in AUC0-tau (at or near steady state).
Nalmefene does not exhibit any substantial pharmacokinetic differences between sexes, between young and elderly, or between ethnic groups.
However, body size seems to affect the clearance of nalmefene to a minor degree (clearance increases with increasing body size), but this is considered unlikely to be of clinical relevance.
Administration of a single oral dose of nalmefene 18.06 mg to patients with mild, moderate or severe renal impairment, classified using the estimated glomerular filtration rate, resulted in an increased exposure to nalmefene relative to that in healthy subjects. For patients with mild, moderate or severe renal impairment the AUC for nalmefene was 1.1 times, 1.4 times and 2.4 times higher, respectively. Further, the Cmax and elimination half-life for nalmefene was up to 1.6 times higher in patients with severe renal impairment. No clinically relevant changes were seen in tmax for any of the groups. For the inactive major metabolite nalmefene 3-O-glucuronide, the AUC and Cmax were up to 5.1 times and 1.8 times higher in patients with severe renal impairment, respectively.
Administration of a single dose of nalmefene 18.06 mg to patients with mild or moderate hepatic impairment increased exposure relative to that in healthy subjects. In patients with mild hepatic impairment, exposure increased 1.5 times and oral clearance decreased by approximately 35%. In patients with moderate hepatic impairment, exposure increased 2.9 times for AUC and 1.7 times for Cmax, while oral clearance decreased by approximately 60%. No clinically relevant changes were seen in tmax or elimination half-life for any of the groups.
Pharmacokinetic data after oral administration of nalmefene to patients with severe hepatic impairment are not available.
No specific study with oral dosing has been conducted in patients ≥65 years of age. A study with IV administration suggested that there were no relevant changes in the pharmacokinetics in the elderly as compared to non-elderly adults.
Nalmefene was shown to have skin sensitisation potential in the Local Lymph Node Assay in mice after topical application.
Studies in animals do not indicate direct harmful effects with respect to fertility, pregnancy, embryonic/foetal development, parturition, or postnatal development.
In a rabbit embryo-foetal developmental toxicity study, effects on foetuses in terms of reduced foetal weight and delayed ossification, but no major abnormalities were seen. The AUC at the no observed adverse effect level (NOAEL) for these effects was below the human exposure at the recommended clinical dose.
An increase in still-born pups and decrease in post-natal viability of pups was observed in prepostnatal toxicity studies in rats. This effect was considered to be an indirect effect related to toxicity to the dams.
Studies in rats have shown excretion of nalmefene or its metabolites in milk.
The nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, or carcinogenic potential.
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